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International Conference of Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH E2E: Pharmacovigilance Planning. 2004; (accessed 1/12/2009) The decision to approve a drug is based on having a satisfactory balance of benefits and risks within the conditions specified in the product labeling. This decision is based on the information available at the time of approval.. The knowledge related to the safety profile of the product can change over time through expanded use in terms of patient characteristics and the number of patients exposed.. In particular, during the early post-marketing period, the product might be used in settings different from clinical trials and a much larger population might be exposed in a relatively short timeframe. Benefits and risk

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Once the product is marketed, new information will be generated, which can have an impact on the benefits or risks of the product; evaluation of this information should be a continuing process, in consultation with regulatory authorities. It is essential that pharmacovigilance be conducted throughout each products lifecycle. Pharmacovigilance should include collecting and evaluating safety data from all available international sources. Benefits and risk (2) Fruijtier A. Pharmaceutical postmarketing and compliance with the marketing authorisation. In Fundamentals of EU Regulatory Affairs Michor S, Rowl K (eds). RAPS Regulatory Affairs Professionals Society: Rockville (MA), 2006; 137–144. EMEA/CHMP/BMWP/42832/05. Committee for medicinal productsfor human use. Guideline on Similar Biological Medicinal Products containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. 2006; [accessed 1/12/2009].http://www.emea.europa.eu CHMP/437/04. Committee for medicinal products for human use. Guideline on Similar Biological Medicinal Products. 2005; [accessed 1 /12/2009].

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Lasser KE et al. JAMA 2002;287: 2215– new chemical entities were approved from of these, 56 (10.2%) drugs acquired a new black box warning or were withdrawn from the market. 42 drugs (8.2%) acquired 1 or more black box warnings that were not present when the drug was approved InKaplan-Meier analyses, the estimated probability of a new drug acquiring black box warnings or being withdrawn from the market over 25 years was 20%. 1 6 drugs (2.9%) approved between 1975 and 2000 were withdrawn from the market between 1975 and had acquired a black box warning prior to withdrawal In Kaplan-Meier analyses, new drugs had a 4% probability of being withdrawn from the market over the study period. Half of withdrawals occurred within 2 years following the drugs introduction.

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Requiring that drugs on the market be completely safe is an impossible goal. The real question is whether the drugs dangers are in some acceptable proportion to the good it does. Jerry Avorn No drug is 100% safe for all people in all circumstances (Organizzazione Mondiale della Sanità)

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The rapidly widespread and often prolonged use of drugs could mean that even a small increase in the risk of a serious adverse event could be very significant in population health terms Every new drug should enter the population of patients in a slow, monitored, and importantly an aselect and noninterventional way, maximising the accumulation of experience and minimising risk exposure. Meyboom RHB, Edwards IR. Lancet 2004; 364:

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Brody H, Light DW. Am J Public Health. 2011;101: 399–404. The inverse benet law, inspired by Harts inverse care law, states that the ratio of benets to harms among patients taking new drugs tends to vary inversely with how extensively the drugs are marketed.

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Aagaard L et al.Drug Saf 2010; 33: To characterize ADRs in children reported in Denmark over a period of one decade. Analysis of ADRs reported to the Danish Medicines Agency from 1998 to 2007 for individuals aged from birth to 17 years. Data were analysed with respect to time, age and sex, category of ADR, seriousness, suspected medicines and type of reporter ADR reports corresponding to 4500 ADRs were analysed. On average, 234 ADR reports were submitted annually, corresponding to approximately two ADRs per report. From 2003 to 2005, an increasing number of ADRs submitted per report were observed, but after 2005 the reporting rate decreased.

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ADRs by age group and number of serious ADRs (1998-–2007). Aagaard L et al.Drug Saf 2010; 33: One-half of ADRs were reported for infants from birth to 2 years of age. Similar total numbers of ADRs were reported for boys and girls

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ADRs distributed by System Organ Class and age group (no. of serious ADRs in parentheses) Aagaard L et al.Drug Saf 2010; 33:

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Reports encompassed medicines from: ATC group J: vaccines and antiinfectives for systemic use (65%); ATC group N: nervous system (17%). On average, 42% of ADRs were classified as serious (28 deaths). ATC group N had the highest proportion of ADRs that were classified as serious. Although physicians reported approximately 90% of the ADRs, a relatively large proportion of serious ADRs were reported by other sources.

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This study investigated perceived ADRs among non-institutionalized children in Germany. All medicines used in the last 7 days before the medical interview were recorded among the children aged 0–17 years who participated in the 2003–06 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Perceived ADRs were reported by the childrens parents and confirmed by trained medical professionals during the medical interview. Knopf H, Du Y. BJCP 2010; 70:

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157 medicines were involved in the occurrence of 198 perceived ADRs in 153 patients. This corresponded to 1.1% of total used drugs, 0.9% (95% CI 0.7, 1.1%) of all children, and 1.7% (1.4, 2.1%) of children treated with medications. About 40% of all perceived ADRs involved gastrointestinal disorders and 16% involved skin tissue disorders. Perceived ADRs were most frequently reported in relation to drugs acting on the nervous system (25.8%), followed by systemic anti-infectives (18.7%) and drugs acting on the respiratory system (16.2%). Risk factors for perceived ADRs included older age groups, polypharmacy (2) and a poor health status. Knopf H, Du Y. BJCP 2010; 70:

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Wallerstedt S et al. Drug Saf 2011; 34: To determine the extent of the spontaneous reporting of ADRs in children with a focus on drugs not used as labelled; this involved investigations of reporting rates of individual case safety reports (ICSRs) per 1000 treated individuals for drugs reported in children, to compare these between drugs labelled and not labelled for use in children, and to compare the rates for children with those of adults. ICSRs (extracted from the Swedish ADR database) and number of treated individuals (extracted from the Swedish Prescribed Drug Register) were analyzed for a 2-year period (2006–7).

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Wallerstedt S et al. Drug Saf 2011; 34: A total of 255 (children) and 1402 (adults) ICSRs concerning 94 drugs were included in the analysis. Seventy-four (29%) and 711 (51%) ICSRs in children and adults, respectively, were registered as serious (p < ). For drugs reported in three or more ICSRs regarding children, the rates of ICSRs per 1000 treated individuals varied between (range) 0.01–6.45 (children) and 0.01–6.39 (adults). For 17 of the drugs (18%) the rates of ICSRs per treated individual were significantly higher for children than for adults, and for 2 of the drugs (2%) the result was the opposite. The overall comparison of aggregated ICSRs per 1000 treated children revealed a higher reporting rate for drugs not labelled than for drugs labelled for children: rate ratio 3.44 (95% CI 2.67, 4.43); p < The corresponding result for adults was 1.52 (95% CI 1.37, 1.68); p < The overall reporting rate of aggregated ICSRs per 1000 treated individuals was higher in children than adults for drugs not labelled for children: rate ratio 2.01 (95% CI 1.61, 2.51); p <

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Adverse Events From Cough and Cold Medications After a Market Withdrawal of Products Labeled for Infants Nadine Shehab N et al., Pediatrics 2010;126; National Electronic Injury Surveillance System Cooperative Adverse Drug Event Surveillance (NIESS-CADES) project: 63 hospitals in USA Surveillance cases: - any incident ED visit by a patient 12 years of age because of a condition that was attributed to a cough and cold medications in the ED medical record that occurred - 14-month (July 22, 2006, to October 11, 2007): period before market withdrawal of orally administered drugs for cough or cold -14-month (October 12, 2007, to December 31, 2008): period after withdrawal. Drugs analyzed decongestant, antihistamine, antitussive, and/or expectorant combinations, as well as single-ingredient decongestants and antitussive agents / expectorants

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Nadine Shehab N et al., Pediatrics 2010;126; Numbers of cases and national estimates of AEs from cough and cold drugs among children <12y treated in EDs before and after withdrawal In the 14-month period after announcementof the withdrawal number and proportion of estimated ED visits for AEs involving children 12y remained unchanged

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Nadine Shehab N et al., Pediatrics 2010;126; National estimates of cough and cold drug-related AEs among children <12 y treated in EDs before and after withdrawal the types of ingestions leading to ED visits for AEs remained relatively unchanged in the prewithdrawal and postwithdrawal periods < 2 y, unsupervised ingestions 59.5% pre- and 52.2% postwithdrawal. among 2-5 y, unsupervised ingestions 83.1% pre and 76.7% postwithdrawal

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Nadine Shehab N et al., Pediatrics 2010;126; National estimates and difference in proprortion of cough and cold drug-related AEs among children <12 y treated in EDs before and after withdrawal a Estimate with coefficient of variation of The contribution of cough and cold medicine to the ED visit burden for all medication-related AEs was significantly reduced (2.1%) for children <2yin the postwithdrawal period, relative to the prewithdrawal period, but remained statistically unchanged (1.1%)for children 2 to 11y

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Star K et al. Drug Saf 2011; 34: To characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. To highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. This was an exploratory study of internationally compiled individual case safety reports (ICSRs). Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010.

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Star K et al. Drug Saf 2011; 34: Reports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.

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Objective To describe the national scope and magnitude of outpatient adverse drug events (ADEs) that lead to emergency department (ED) visits in children and adolescents. Study design To conduct an active surveillance of patients 18 years of age or younger who came to EDs with ADEs, through a nationally representative, stratified probability sample of 63 US hospitals with EDs. Period Jan 1, Dec 31, 2005 The main outcome measures were national estimates of the number, type, patient demographics, and clinical characteristics of ADEs. National Surveillance of Emergency Department Visits for Outpatient Adverse Drug Events in Children and Adolescents (Cohen AL. et al. J Pediatr 2008; 152: 416–21)

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Association Between Second-Generation Antipsychotics and Changes in Body Mass Index in Adolescents Ghate SR et al, Journal of Adolescent Health 2013; 52: Purpose: To assess the association of second generation antipsychotics (SGAs) with changes in BMI) among adolescents compared with a matched untreated comparison group. Methods: A retrospective cohort study was conducted using an electronic medical record database between January 2004 and July Adolescents (12e19 years old), newly initiated on SGAs formed the exposure group and untreated adolescents formed the comparison group matched (3:1) to the antipsychotic group based on age, gender, and month of index SGA. Both the exposure and comparison groups were followed for slightly more than a year (395 days). Baseline and follow up BMI were evaluated for both groups and percentage change from baseline BMI to follow up BMI was calculated. Multivariate linear regression was conducted to assess the impact of SGAs on percent change in follow up BMI from baseline controlling for demographic characteristics, baseline medications, comorbidities, and other covariates.

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Association Between Second-Generation Antipsychotics and Changes in Body Mass Index in Adolescents Ghate SR et al, Journal of Adolescent Health 2013; 52: Results: The mean percentage increase in follow up BMI from baseline for antipsychotic group was significantly higher than the comparison group (p< 0.01). After adjusting for covariates, adolescents on olanzapine had the highest percentage increase in follow up BMI from baseline [5.84%, ( )] followed by aripiprazole [4.36%( )], risperidone [3.65% ( )], and quetiapine [1.53% ( ) compared with the comparison group. Conclusion: This study further validates a growing concern of increased BMI in adolescents on SGA therapy.

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Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED) visits for AE due to systemic antibiotics, by patient and case characteristics- US

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Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED visits for AE associated with systemic antibiotics, by drugUnited States, 2004–2006 (1).

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Clin Infec Dis 2008; 47:735–43. Number of cases and national estimates of ED visits for AE associated with systemic antibiotics, by drugUnited States, 2004–2006 (2).

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Number of cases and national estimates of the rate of emergency department (ED) visits for adverse events associated with a single systemic antibiotic class, by adverse event conditionUnited States, 2004–2006. Clin Infec Dis 2008; 47:735–43.

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Emergency Department Visits for Antibiotic-Associated AE Shehab N, Patel PR, Srinivasan A, Budnitz DS. Clin Infec Dis 2008; 47:735–43. Conclusions Antibiotic-associated adverse events lead to many ED visits, and allergic reactions are the most common events. Minimizing unnecessary antibiotic use by even a small percentage could significantly reduce the immediate and direct risks of drug-related adverse events in individual patients

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Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e803 OBJECTIVE: To determine whether childhood antianaerobic antibiotic (penicillin, amoxicillin, ampicillin, penicillin/b-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin) exposure is associated with the development of inflammatory bowel disease (IBD). METHODS: This retrospective cohort study employed data from 464 UK ambulatory practices participating in The Health Improvement Network. All children with >2 years of follow-up from 1994 to 2009 were followed between practice enrollment and IBD development, practice deregistration, 19 years of age, or death; those with previous IBD were excluded. All antibiotic prescriptions were captured.

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A, Proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure status.P,.001 for the difference between groups by using the log-rank test. B, proportion of subjects developing IBD according to age and antianaerobic antibiotic exposure level. P,.001 for the difference among groups by using the log-rank test. Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

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Hazard of developing IBD if ever previously exposed to antianaerobic antibiotics, according to age Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e e803

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Antibiotic Exposure and IBD Development Among Children: A Population-Based Cohort Study Kronman MP et al Pediatrics 2012;130:e794–e803 CONCLUSIONS: Exposure to antianaerobic antibiotics during childhood was associated with development of the lifelong autoimmune condition IBD. This study suggests that reduction in childhood antianaerobic antibiotic use may have the potential to help curb the rising incidence of childhood IBD.

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Ciprofloxacin safety in paediatrics: a systematic review AdefurinA et al; Arch Dis Child 2011;96:874–880. Objective To determine the safety of ciprofl oxacin in paediatric patients in relation to arthropathy, any other adverse events (AEs) and drug interactions. Methods A systematic search of MEDLINE, EMBASE, CINAHL, CENTRAL and bibliographies of relevant articles was carried out for all published articles, regardless of design, that involved the use of ciprofl oxacin in any paediatric age group 17 years. Only articles that reported on safety were included.

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Nonsteroidal Anti-Inflammatory Drugs Are an Important Cause of Acute Kidney Injury in Children Misurac JM et al, J Pediatr 2013 Objective To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. Study design A retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code or from January 1999 to June Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development.

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Emergency Department Visits for Overdoses of Acetaminophen- Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Purpose: To estimate the frequency of and characterize risks for emergency department visits foracetaminophen overdoses that were not related to abuse in the U.S. Methods: Data were collected from two components of the National Electronic Injury Surveillance System from January 1, 2006, through December 31, 2007, and analyzed from 2009 to 2010 to estimate the annual number of emergency department visits for: a)non-abuse-related acetaminophen b)overdose by patient demographics, c)treatments, d)and type and amount of acetaminophen-containing product ingested.

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Emergency Department Visits for Overdoses of Acetaminophen-Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 The population rate of emergency department visits for unsupervised ingestions among children aged 6 years was second to only the rate of emergency department visits for self-directed violence by those aged 15–24 years, and nearly one third of unsupervised ingestions were treated with NAC or gastrointestinal decontamination. Most of these unsuperunsupervised ingestions were by children aged 6 years, and slightly more than half of emergency department visits for unsupervised ingestions of acetaminophen were attributed to ingestion of pills. Unsupervised Ingestion

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Emergency Department Visits for Overdoses of Acetaminophen-Containing Products Budnitz DS et al., Am J Prev Med 2011;40:585–92 Therapeutic misadventures accounted for 16.7% of emergency department visits for acetaminophen overdoses, and most therapeutic misadventures (56.1%) involved overuse of an acetaminophen product for a medicinal effect. Previous studies of patient knowledge and practices have found that oftentimes, individuals are not aware of the potential harm from taking or administering acetaminophen improperly. Among adolescents and young adults, overuse of an acetaminophen product for more potent medicinal effects was documented in three fourths of emergency department visits attributed to therapeutic misadventures, and three fourths of therapeutic misadventures involved OTC formulations. On the other hand, among older adults, more than four fıfths of therapeutic misadventures involved acetaminophen– opioid combination products. Thus, these data sugges that to reduce the incidence of emergency department visits for therapeutic misadventures, interventions should target safe practices in the use of OTC medications by adolescents and young adults and safe use of acetaminophen– opioid combination products by older adults. Therapeutic Misadventure

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Prevalenza dellasma pediatrica Between 1980 and 2003, the prevalence of pediatric asthma in the US increased from 3.6% to 5.8%, and similar increases were observed throughout the world. Asthma prevalence leveled off in the 1990s at a time in which acetaminophen had already become the most commonly used analgesic/antipyretic for children. Although other changes in the environment have been suggested that might explain an increase in childhood asthma, including the hygiene hypothesis, none so easily explains the rapid increase in asthma in the 1980s and the subsequent leveling off of asthma prevalence over the last 15 years. (Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med. 2006;355: 2226 –35) Furthermore, the prevalence of childhood wheezing in 36 countries around the world is predicted by each countrys per-capita sales of acetaminophen. (Newson RB et al; Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J. 2000;16:817– 23)

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Acetaminofene / Paracetamolo e asma

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ISAAC Phase Three Study Group. Acetaminophen (AC) use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents (1) Beasley RW et al; Am J Respir Crit Care Med. 2011;183:171–8 122 centers in 54 countries, each study site enrolled at least 1000 children. The investigators rigorously identified children with wheezing and asthma symptoms and also collected data on AC exposure and other environmental factors that potentially contribute to the pathogenesis or severity of asthma. Data available children aged 6 to 7 years children aged 13 to 14 years. (Nearly 30% reported t aking AC at least once per month) In both age groups there was AC dose-dependent increase in the prevalence and severity of asthma. For 6- to 7-year-olds, the risk of current asthma was increased fold ( ) for those who took AC more than once per year but less than once per month fold (2.91–3.60) for those who took AC at least once per month. For 13- to 14-year-olds the risks of current asthma was increased 1.43 (95% CI: 1.33–1.53) for those who took AC more than once per year but less than once per month 2.51 (95% CI: 2.33–2.70 for those who took AC at least once per month Studi epidemiologici

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ISAAC Phase Three Study Group. Acetaminophen (AC) use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents (2) Beasley RW et al; Am J Respir Crit Care Med. 2011;183:171–8 For each age cohort, the investigators calculated a population-attributable risk (PAR) for AC exposure. This parameter estimates the reduction in incidence of asthma or asthma symptoms that would occur in the entire population if exposure to AC were eliminated, assuming that AC does exacerbate asthma. For 6- to 7-year-olds the PAR for severe asthma symptoms = 38%; For 13- to 14-year-olds, the PAR for current wheeze = 41% The PAR for severe asthma symptoms = 43%. Studi epidemiologici

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ACETAMINOPHEN (AC): EPIDEMIOLOGIC STUDIES IN CHILDREN in Ethiopia and New Zealand An Ethiopian population-based cohort study revealed that a high rate of AC use among 1- and 3-year-olds (36% and 42%, respectively) and an association between AC use and wheeze are not limited to urban/industrial environments. (Amberbir A et al., The role of acetaminophen and geohelminth infection on the incidence of wheeze and eczema: a longitudinal birth- cohort study. Am J Respir Crit Care Med. 2011;183:165–170) In a group of 5- to 6-year-old children in New Zealand, use of 10 doses of AC per year was associated with an increased risk of current asthma (OR: 2.83 [1.63– 4.88]) Wickens K et al; New Zealand Asthma and Allergy Cohort Study Group. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clin Exp Allergy. 2011;41: 399–406 Studi epidemiologici

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Acetaminophen use and the risk of asthma in children and adults: a systematic review and meta-analysis. Etminan M et al; Chest. 2009; 136:1316 –1323 Meta-analysis of 6 other epidemiologic studies in children (27000 subjects) calculated a pooled odds ratio for wheezing in the previous year of 1.97 (95% CI: 1.51– 2.56) related to acetaminophen use Studi epidemiologici

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Asthma morbidity after the short-term use of ibuprofen in children. Lesko SM et al Pediatrics. 2002; 109(2). Available at: cgi/content/full/109/2/e20 Between 1991 and 1993 the Boston University Fever Study randomly assigned nearly febrile children aged 6 months to 12 years to receive, as necessary, low-dose ibuprofen, high-dose ibuprofen, or acetaminophen (12 mg/kg per dose) in a double blind fashion. Of these children, 1879 with preexisting asthma were nearly evenly assigned among the 3 groups. For asthmatic children with a respiratory infection, the subsequent need for an outpatient asthma visit was 2.3 times higher in those treated with acetaminophen (95% CI: 1.26–4.16), and the risk was dose-dependent. Because there was no placebo control, it is theoretically possible that this outcome was a result of a protective action of ibuprofen, but the acetaminophen dose dependence, the lack of dose dependence for ibuprofen, and the availability of other evidence that acetaminophen exacerbates asthma make this explanation unlikely PROSPECTIVE TRIALS

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Prospective study of acetaminophen use and newly diagnosed asthma among women Barr et al; Am J Respir Crit Care Med. 2004; 169:836–41 In 1990 and 1992, female nurses who were enrolled in the Nurses Health Study were asked about their use of acetaminophen and similar medications as well as known diagnoses. By 1996, 346 women who did not report a diagnosis of asthma at enrollment had a new physician diagnosis of asthma. There was a dose dependent increase in the risk of developing asthma among women exposed to acetaminophen and little relationship to aspirin or NSAIDs. Women who took acetaminophen14 days/month, were 1.63 (1.11–2.39) times as likely to have developed asthma as those who did not take acetaminophen. PROSPECTIVE TRIALS

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The Association of Acetaminophen and Asthma Prevalence and Severity McBride JT, Pediatrics 2011;128: The epidemiologic association between acetaminophen use and asthma prevalence and severity in children and adults is well established and seggested by the: 1.strength of the association; 2.consistency of the association across age, geography, and culture; 3.dose-response relationship; 4.timing of increased acetaminophen use and the asthma epidemic; 5.the relationship between per-capita sales of acetaminophen and asthma prevalence across countries; 6.results of a double-blind trial of ibuprofen and acetaminophen for treatment of fever in asthmatic children; 7.biologically plausible mechanism of glutathione depletion in airway mucosa. Children with asthma or at risk for asthma should avoid the use of acetaminophen.

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La percezione del generico There is an extensive publicity suggesting that generic prescribing is potentially problematic. A patient knowing that a generic is being prescribed might view this in a very negative way and might have an increased tendency to attribute any adverse event to the change. If a recent switch to a generic has been made, the patient might even be more likely to call on the emergency services because of increased anxiety. This is the negative placebo or nocebo effect, the opposite of a placebo effect Generic antiepileptic drugs and increased health care utilization. Fact or myth? Besag FMC. Neurology 2010; 74:

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La percezione del valore di un farmaco (placebo/nocebo) This nocebo effect, is the opposite of a placebo effect. Instead of the patient thinking that the medication might do good, the patient thinks that the medication or, in this case, switch to the medication, might do harm. Any negative change is consequently likely to be attributed to the generic. Generic antiepileptic drugs and increased health care utilization. Fact or myth? Besag FMC. Neurology 2010; 74: